One of the most well-known and widely used of the classes of antibacterial agents is the class known as the .beta.-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (.beta.-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxylmethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the .beta.-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given .beta.-lactam antibiotic results because the microorganism produces a .beta.-lactamase. The latter substances are enzymes which cleave the .beta.-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit .beta.-lactamases, and when a .beta.-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increease or enhance the anti-bacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a .beta.-lactamase inhibiting substance and a .beta.-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.
Thus, according to the invention, there are provided certain new chemical compounds which are new members of the class antibiotics known as the penicillins, and which are useful as antibacterial agents. More specifically, these new penicillin compounds are penicillanic acid 1,1-dioxide, and esters thereof readily hydrolyzable in vivo.
Additionally, penicillanic acid 1,1-dioxide and its esters readily hydrolyzable in vivo are potent inhibitors of microbial .beta.-lactamases. Accordingly, there is also provided a method for enhancing the effectiveness of .beta.-lactam antibiotics, using penicillanic acid 1,1-dioxide and certain readily hydrolyzable esters thereof.
Still further, there are provided derivatives of penicillanic acid 1,1-dioxide having a carboxy protecting group, said compounds being useful as chemical intermediates for penicillanic acid 1,1-dioxide.
Yet further, there are provided penicillanic acid 1-oxides, and certain esters thereof, as chemical intermediates to penicillanic acid 1,1-dioxide.
1,1-Dioxides of benzylpenicillin, phenoxymethylpenicillin and certain esters thereof have been disclosed in U.S. Pat. Nos. 3,197,466 and 3,536,698, and in an article by Guddal et al., in Tetrahedron Letters, No. 9, 381 (1962). Harrison et al., in the Journal of the Chemical Society (London), Perkin I, 1772 (1976), have disclosed a variety of penicillin 1,1-dioxides and 1-oxides, including methyl phthalimidopenicillanate 1,1-dioxide, methyl 6,6-dibromopenicillanate 1,1-dioxide, methyl penicillanate 1.alpha.-oxide, methyl penicillanate 1.beta.-oxide, 6,6-dibromopenicillanic acid 1.alpha.-oxide and 6,6-dibromopenicillanic acid 1.beta.-oxide. Belgian Pat. No. 866,845, granted Nov. 9, 1978, discloses penicillanic acid 1-oxide having the carboxy group protected by a carboxy protecting group.